Colorectal cancer is one of the most common malignancies and is the second leading cause of cancer death in the United States. Most of these cancers arise from adenomatous polyps. Factors involved in one-carbon metabolism and aberrations in methylation reactions have been implicated in previous studies of colorectal neoplasia. Methionine metabolism is a key component in one-carbon metabolism and it is integrally involved in most physiologic methylation reactions including DNA and RNA methylation. S-adenosylhomocysteine (SAH), the precursor to homocysteine, has been proposed as a more sensitive marker of alterations in methionine metabolism than homocysteine. Additionally, the ratio of S-adenosylmethionine (SAM) to SAH is a marker of methylating capacity and a lower SAM: SAH is related to increased DNA hypomethylation. However, neither of these markers has been evaluated in relation to cancer risk. We hypothesize that a high SAH level and a low SAM: SAH ratio are associated with an increased risk of colorectal adenoma. In this proposed study, we will evaluate these hypotheses by conducting a nested case-control study using plasma samples collected as part of the Tennessee Colorectal Polyp Study (TCPS;P50CA95103), an on-going colonoscopy-based case-control study of colorectal adenoma. We will measure SAH and SAM levels in 265 cases and 265 matched controls. The hypotheses proposed in the application are novel and based on strong biological plausibility. Results from this study will not only be useful to understand one-carbon metabolism and colorectal neoplasia but also be informative for developing a sensitive biomarker for identifying high-risk individuals for cost-effective colorectal screening and chemoprevention.